tbuckley/cabot-search huggingface dataset:
Abstract 13973: Human iPSC-Derived Multi-Cell-Type Engineered Heart Tissues as an <i>in vitro</i> Model to Study Pathological Cardiac Hypertrophy
Authors: Kinga M Wrona, Alba M. M Albert, Dominik Eckardt, Christoph Herbel, Julia Krause, Jutta Starbatty, Sandra A A Hemkemeyer, Maike Frye, Friederike Cuello, Thomas Eschenhagen, Marc N Hirt
Journal: Circulation (2022)

Introduction Pathological cardiac hypertrophy has not been fully recapitulated in the in vitro settings. Currently used in vitro models are presumably oversimplified since the vast majority are based on iPSC-derived cardiomyocytes (CMs) exclusively and do not include any cardiac non-myocytes. The aim of this study was to generate engineered heart tissues (EHTs) containing five hiPSC-derived cardiac cell types, i.e., CMs, endothelial cells (ECs), macrophages (Mϕs), fibroblasts (FBs), and smooth muscle cells (SMCs) and treat them with prohypertrophic compounds. Methods: Mesoderm induction preceded all cell-type-specific differentiation steps. CMs were then generated by Wnt signaling inhibition and ECs by VEGF stimulation. Mϕ differentiation required treatment with IL-3+M-CSF. FBs and SMCs were generated by Wnt pathway activation followed by bFGF or TGFβ+bFGF stimulation. The characterization of different iPSC-derivatives and EHTs was based on the MICS (MACSima Imaging Cycling Staining) technology and profiling of hallmark genes and proteins. To study the response to prohypertrophic stimuli, EHTs were treated with 20 μM phenylephrine (PE) and 50 nM endothelin-1 (ET-1) for 9-10 days. Results: The expression of cell-type-specific markers and functional assays were the determinants of successful differentiation. For instance, CMs were identified based on cTnT expression and contractile capabilities, Mϕs by expression of CD68 and phagocytic activity, and ECs by CD31 expression and tube formation abilities. Multi-cell-type EHTs were assembled from 60% CMs, 20% ECs, 10% Mϕs, 5% FBs and 5% SMCs. These EHTs displayed accelerated development, i.e., faster remodeling and earlier onset of beating compared to CM-only EHTs. Preliminary results show that multi-cell-type EHTs exhibited higher maximal forces and increased stiffness compared to CM-only controls. The exposure to PE+ET-1 led to a decrease in force, activation of the hypertrophic gene program, and elevation of NT-pro BNP production. Conclusions: We successfully generated functional multi-cell-type EHTs containing five hiPSC-derived cardiac cell types. Upon hypertrophic stimulation, these EHTs developed a pathological phenotype that resembles the hallmarks of a failing human heart.
Abstract 14026: Intermittent Occlusion of the Superior Vena Cava Reduces Estimated Stressed Blood Volume in Patients With Acutely Decompensated Heart Failure
Authors: Rayan Yousefzai, Jacob Abraham, Michael S Kiernan, Ryan J Tedford, Keith Benzuly, Richard H Karas, Daniel Burkhoff, Navin K Kapur
Journal: Circulation (2022)

BACKGROUND: Stressed blood volume (SBV) refers to intravascular volume that produces hydrostatic pressure and contributes to congestion in acutely decompensated heart failure (ADHF). The VENUS HF Early Feasibility Study (EFS) is the first clinical trial testing intermittent occlusion of the superior vena cava (SVC) with the preCARDIA system, a catheter mounted balloon and pump console, to improve decongestion in ADHF. We hypothesized that preCARDIA therapy reduces SBV in ADHF. Methods: In a multicenter, prospective, single-arm exploratory safety and feasibility trial, 32 patients with ADHF were assigned to preCARDIA therapy for 24 hours. Invasive hemodynamics were measured before, immediately after, and for 3 hours after preCARDIA treatment. SBV was estimated (eSBV) using the hemodynamic simulator, Harvi, with heart rate (HR), cardiac output (CO), central venous pressure (CVP), pulmonary capillary wedge pressure (PCWP), systolic and diastolic systemic arterial and pulmonary artery (PA) pressures, and left ventricular ejection fraction (LVEF) from 27 enrolled subjects. Results: Mean LVEF was 28±13%. Freedom from device or procedure related major adverse events was observed in 96% (n=26/27) of patients. Compared to pre-treatment values, CVP, PCWP, and PA pressures were significantly reduced, while systemic mean arterial pressures, HR and CO remained unchanged (Table 1). Daily urine output (2.6±1.9 vs 5.2±3.8 L, p=0.0072) and net fluid balance (-1.7±1.4 vs -3.4±2.6 L/24hr, p=0.0098) improved with 24-hours of treatment. Compared to pre-treatment values, eSBV decreased by 22% or -709±551 mL/70kg from baseline to 3 hours after treatment completion (3217±426 vs 2507±694 mL/70kg, p&lt;0.000001). Conclusions: We report for the first time that intermittent SVC occlusion using the preCARDIA system reduced estimated stressed blood volume in patients with ADHF. These results support future studies characterizing the clinical utility of the preCARDIA system.
Abstract 14391: The Transcriptional Landscape of Liver Sinusoidal Endothelial Cells
Authors: Pablo Toledano Sanz, Paula Reventun, Maria Viskadourou, William Osburn, Nunzio Alcharani, Charles J Lowenstein, Marios Arvanitis
Journal: Circulation (2022)

Introduction: Human liver endothelial cells (HLEC) are a heterogeneous cell population. Single cell transcriptomics and immunostaining assays have categorized HLEC into two major groups according to their location within the liver lobules (zone 1 or periportal HLEC and zones 2/3 or central venous (CV) HLEC). Hypothesis: Cellular deconvolution of the bulk transcriptome of HLEC will highlight important properties of HLECs and their transcriptional regulators. Methods: We uniformly processed all bulk RNA-seq data from HLECs in Gene Expression Omnibus. We used CIBERSORTx with human liver single cell RNA-seq data to perform cell type deconvolution of bulk HLEC RNA-seq. We compared the transcriptome of HLEC subpopulations to that of HUVEC. We then applied the HOMER motif finding algorithm on the promoters of genes up/downregulated in HLEC compared to HUVEC. Results: We analyzed data from 10 HLEC samples and 107 HUVEC samples from 37 independent experiments. Principal component analysis revealed that 6 of the 10 HLEC samples have robust transcriptional differences compared to HUVEC. CIBERSORTx showed that those 6 HLEC samples correspond to CV HLECs and can be identified by FCGR2B expression. Differential gene expression analysis revealed enrichment of inflammatory and coagulation pathways in CV HLEC and enrichment of proliferation and mitosis pathways in HUVEC. CV HLEC showed increased expression of factors VIII, X, XII, Protein S and antithrombin III. We validated gene expression at the protein level by Western blot. A transcription factor (TF) prioritization approach using HOMER motif enrichment revealed a potential role for E2F, and RXR-RAR TF as primary determinants of the differences between HUVEC and CV HLEC. Conclusions: We identify and characterize CV HLEC as a distinct endothelial subtype relevant to inflammation and coagulation. We also identify downregulation of E2F and upregulation of RXR-RAR TF as potential key regulators of the CV HLEC transcriptome.
Abstract 14027: Use of Anticoagulation or Antiplatelets in Patients With Cardiac Arrest Without ST-Segment-Elevation or Percutaneous Coronary Intervention
Authors: Muhammad H Maqsood, Kumar Ashish, David X Zhao, Syed T Rab, Saraschandra Vallabhajosyula
Journal: Circulation (2022)

Introduction: There are limited data on the use of anticoagulation (AC) and anti-platelet (AP) agents in addition to aspirin compared to standard of care (aspirin alone) in cardiac arrest (CA) patients without ST-segment-elevation and not undergoing a percutaneous coronary intervention. Hypothesis: We hypothesized that use of AC/AP agents in CA is associated with lower mortality compared to aspirin alone. Methods: A comprehensive literature search was performed from inception to 09/30/2021 of the PubMed/EMBASE databases. Studies of adult patients comparing AC/AP to aspirin alone were evaluated for short-term mortality (30-days survival/survival to hospital discharge), significant bleeding, and return of spontaneous circulation (ROSC). Odds ratio (OR) with 95% confidence intervals (CI) were calculated using DerSimonian-Laird method. Results: Of a total 5337 studies, five studies (2 randomized trials and 3 observational studies) with 3,696 subjects (1,196 intervention and 2,500 placebo arm) were included. Overall, there was no evidence of publication bias using either funnel plot or eggers test. For RCT studies, mean age was 60.8 years (males 79.2%), while for observational study mean age was between 58 to 62.3 years (males 58-62.3%). Use of AP/AC was associated with higher rates of major bleeding (odds ratio [OR] = 2.43 [95% confidence interval {CI} 1.35- 4.37]; p=0.003; I2=7%; 4 studies) compared with aspirin alone. There was no significant difference in ROSC (OR= 1.24 [95% CI 0.68-2.26]; p=0.49; I2=57%; 3 studies) and short-term mortality [OR= 1.24 [95% CI 0.87-1.76]; p=0.24; I2=69%; 3 studies) between intervention and placebo arm. Conclusions: In this meta-analysis, use of concomitant AC/AP therapy with aspirin in CA without ST-segment-elevation or percutaneous coronary intervention was associated with higher rates of bleeding without improvement in short-term mortality or ROSC.
Abstract 14352: Variations in Spontaneous Coronary Artery Dissection Diagnosis Based Upon Hospital Status
Authors: Mohsin S Mughal, Muhammad Tayyeb, Hasan Mirza, Hafsa Akbar, David M Anwar, Mohammed Haris Usman, Fahad Waqar, Ali Ghani, najam wasty
Journal: Circulation (2022)

Background: Spontaneous coronary artery dissection (SCAD) contributes to a significant number of acute coronary syndrome (ACS) in middle-aged female. SCAD data are accumulating to understand its epidemiology, etiology, presentation, and diagnosis. Despite the rising incidence, there is limited data regarding the number of diagnosed cases based on hospital location. We hypothesized that more cases of SCAD are diagnosed at teaching urban hospitals than urban non-teaching or rural hospitals. Methods: In this retrospective study, the discharge data were extracted from the National Inpatient Sample (NIS), and Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality from 2010 to 2017. We used the 9th and the 10th revisions of International Classification Disease (ICD-9-CM code 414.12, ICD-10-CM Code I25. 42) for SCAD. SCAD cases per year (weighted to represent nation sample) were collected and stratified by hospital location (urban teaching, urban non-teaching, and rural). p - value was calculated by Cochran-Armitage test. A p -value of &lt;0.05 was considered significant and all p-values were two-sided. Results: We found a total of 490 patients with a primary diagnosis of SCAD. The numbers were weighted to present a national total of 2432 discharges. Demographic characteristics are shown in table-1. Year-year SCAD cases quantified by rural, urban teaching, urban non-teaching status are shown in table-1. Of these 2432 discharges, 72.34% were at the urban teaching hospitals, followed by 25.05% at urban non-teaching hospitals, and only 2.6% were at rural hospitals. This difference was statistically significant (p -value &lt;0.001). Conclusions: A higher number of SCAD cases at urban teaching hospitals may indicate the diagnosis bias due to better availability of expertise and advanced modalities to diagnose this entity at urban teaching hospitals.
Abstract 14367: Residual Cardiovascular Risk Despite Secondary Prevention: Data From Contemporary Cardiovascular Outcomes Trials Spanning 2010 - 2021
Authors: Serge Korjian, Yazan Daaboul, Deepak L Bhatt, Paul M Ridker, Robert W Yeh, Roxana Mehran, Suzanne J Baron, Peter Libby, Gerald Chi, Arzu Kalayci, Paul Nara, Alka Shaunik, C. Michael Gibson
Journal: Circulation (2022)

Introduction: Despite aggressive secondary prevention, a persistent risk of cardiovascular (CV) events exists among patients with coronary artery disease (CAD). In addition to traditional risk factors, this residual risk results, at least in part, from persistent pro-inflammatory and metabolic contributors. This study evaluated the incidence of recurrent CV events in contemporary CV outcome trials between 2010-2021. Methods: A total of 45 randomised, controlled trials were included. Studies were categorized based on patient population and enrollment strategy into 3 groups: 1) Early post-ACS (enrolled within 72h of event), 2) late post-ACS (enrolled after 72h of event), and 3) chronic CAD or risk equivalent (type 2 diabetes or 2 or more CV risk factors). Due to a wide range of follow-up durations, data were normalized to events per 100 patient-years. Results: Follow-up duration ranged from 30 to 2957 days. Overall, recurrent CV events varied between 2% and 10%. Trials that enrolled patients within 72h of ACS demonstrated the highest risk for recurrent events with a median of 21.8 events per 100 patient-years (IQR 11.3-66.0). Patients enrolled &gt;72h after ACS had significantly lower risk with a median of 3.4 events per 100 patient-years (IQR 2.9-4.1), likely due to a survival bias in those enrolled later after their index event. The rate of recurrent events was comparable between trials that enrolled patients 72h post-ACS and trials that enrolled patients with chronic CAD. There was no correlation between trial year and event rate. Conclusions: Despite standard of care therapy, there is a persistent residual risk of recurrent events especially early after ACS. Our study demonstrates a residual risk ranging from 3 to as high as 22 events per 100 patient-years. This risk is likely higher in a non-trial setting where medication adherence and follow-up are not strictly controlled. Novel strategies for secondary prevention comprise a major unmet need to further decrease this risk.
Abstract 12757: Competing Neurotrophic and Anti-Neurotrophic Remodeling Processes in PVC-Induced Cardiomyopathy
Authors: Rahul Myadam, Li Wang, Jaime B Villalobos, Juana Maria de Lourdes Medina Contreras, Anindita Das, Karoly Kaszala, Kenneth Ellenbogen, Jose Eltit, Jose F Huizar, Alex Y Tan
Journal: Circulation (2022)

Introduction: We previously demonstrated evidence of pro-arrhythmic sympathetic hyperinnervation and hyperactivity of the stellate ganglia in Premature Ventricular Contraction-induced Cardiomyopathy (PVC-CM). However, the presence of neural remodeling within the myocardium remains unclear. Methods: In a canine model of PVC-CM induced by a novel premature pacing algorithm with 12-weeks of bigeminal short-coupled (200ms) PVC exposure, we performed ELISA of serial plasma norepinephrine levels at baseline vs PVC-CM (N=7), and western blotting of neural proteins and beta-adrenoreceptors using snap-frozen left ventricular free wall myocardium in 6 sham controls and 7 PVC-CM hearts. Results: We found increased trans-cardiac norepinephrine (NE) levels in PVC-CM vs controls (Fig. 1A), increased LV myocardial sympathetic nerve protein Tyrosine Hydroxylase (TH) (Fig.1B) but interestingly, decreased Growth Associated Protein (GAP) 43 (Fig.1C), a marker of sprouting nerve cones. There was no change in synaptophysin (SYN), a neural synapse protein, or Choline acetyltransferase (ChAT), a parasympathetic nerve marker (Fig.1D). Further downstream, we found reduced ß-1 receptor levels similar to other forms of heart failure but markedly increased ß-2 receptor levels (Fig.1E), a finding unique to PVC-CM. Functionally, ß-2 effects are known to oppose the ß-1 inotropic and pro-apoptotic effects in the human myocardium Conclusions: There are competing neurotrophic vs anti-neurotrophic processes occurring within the LV myocardium, along with downstream beta-receptor changes. We hypothesize that these changes are a chronic adaptive response to PVC-induced chronic sympathetic surge, that ultimately protect against sympathetic excess and its consequent downstream effects on myocardial calcium handling and inotropy. These changes may have implications for the pathogenesis of PVC-CM and its pro-arrhythmic consequences. !
Abstract 14310: Patient Reported Outcomes of Catheter Ablation for Atrial Fibrillation in Patients With Chronic Kidney Disease
Authors: Medhat Farwati, Brett Johnson, mustapha amin, Amr Farwati, Mustafa Turkmani, Hiroshi Nakagawa, Walid I Saliba, Khaldoun Tarakji, Mohamed Diab, Shunsuke Kuroda, Mohamed H Kanj, Thomas J Dresing, Thomas D Callahan, Mandeep Bhargava, Bryan Baranowski, John Rickard, Daniel J Cantillon, Patrick Tchou, Oussama M Wazni, Ayman Hussein
Journal: Circulation (2022)

Introduction: Increasingly, catheter ablation for atrial fibrillation (AF) has been utilized for rhythm control and to improve quality of life (QoL). Data are limited on patient-centered ablation outcomes in individuals with chronic kidney disease (CKD). Objective: To examine clinical outcomes and QoL following AF ablation in CKD patients from a large patient-reported outcomes (PRO) database. Methods: All patients undergoing AF ablation (2013-2016) at our center were enrolled and assessed for outcomes using automated PRO surveys (baseline, 3 and 6 months after ablation, every 6 months thereafter). This analysis captured data at 1- and 3-year follow-up. CKD was defined as estimated glomerular filtration rate (eGFR) &lt;60 ml/min using the 2021 CKD-EPI equation. The atrial fibrillation symptom severity scale (AFSSS) was used as the main measure for QoL assessment. In addition, data were collected on clinical improvement by patient report, AF burden, and healthcare utilization. Results: A total of 488 patients were identified (66% male, mean age 68.5, 56.2% persistent AF). QoL was significantly improved from baseline median (IQR) AFSSS of 14 (6-19.5) to 3 (0-9) at 1-year and 4 (0-9.5) at 3-year; P≤0.0001 for both. About 90% of patients reported improvement in their overall AF-related symptoms both at 1- and 3-year follow up. The proportion of patients in AF at the time of completion of the baseline survey was 51.2%, and this decreased to 6.2% at 1-year and 9.7% at 3-year follow up (P&lt;0.0001 for both). AF burden was significantly reduced at 1-year and 3-year including frequency and duration of episodes (P&lt;0.05 for both), with associated decrease in ER visits and hospitalizations; P&lt;0.0001 for all comparisons. The proportion of patients on antiarrhythmics decreased from 61.8% at baseline to 35.6% and 22.7% at 1-year and 3-year, respectively (P&lt;0.0001 for both). Conclusions: In a large AF-specific PRO system, catheter ablation for AF was associated with a significant improvement of QoL in most patients with CKD; with a decrease in AF burden and healthcare utilization.
Abstract 13262: Phytosterol Intake and Risk of Coronary Heart Disease in U.S. Men and Women
Authors: Yeli Wang, Yang Hu, Laura Sampson, Joann E Manson, Eric B Rimm, Qi Sun
Journal: Circulation (2022)

Introduction: Phytosterols are structurally similar to cholesterol and partially inhibit intestinal absorption of cholesterol. Evidence regarding dietary phytosterols in relation to coronary heart disease (CHD) risk remains limited. We aimed to prospectively assess the associations between total and individual phytosterol intake and CHD risk in U.S. men and women. Methods: A total of 214,108 men and women from the Nurses’ Health Study (NHS), NHSII, and Health Professionals Follow-Up Study without cardiovascular disease or cancer at baseline were included in the analyses. Diet was assessed using a validated food frequency questionnaire every 2-4 years since baseline. Cox proportional hazards regression models were used to evaluate associations between phytosterol intake and CHD risk. Results: During 5,516,455 person-years of follow-up, 10,152 CHD cases were documented. Comparing extreme quintiles, pooled hazard ratios (HRs) (95% CIs) of CHD were 0.91 (0.85-0.98; P -trend=0.08) for total phytosterols, 0.88 (0.82-0.95; P -trend=0.02) for campesterol, 0.96 (0.90-1.02; P -trend=0.22) for stigmasterol, and 0.91 (0.84-0.98; P -trend=0.03) for beta-sitosterol. Nonlinear associations were observed for total phytosterols, campesterol, and beta-sitosterol: the risk reduction plateaued at intakes above ~180 mg/day, 30 mg/day, and 130 mg/day, respectively ( P -nonlinearity&lt;0.001). Among 23,543 participants with existing CHD risk markers, phytosterol intake was inversely associated with plasma levels of total cholesterol, triglycerides, C-reactive protein, and interleukin-6, and was positively associated with adiponectin. Phytosterol intake was not associated with LDL or HDL cholesterol levels. Conclusions: Higher long-term intake of total and major subtypes of phytosterols was associated with modest CHD risk reduction, which may plateau at moderate intake levels. The role of phytosterols in preventing CHD needs further investigation.
Abstract 12814: Atrial Fibrillation Risk Prediction Through Integration of Imaging-Based Biomarker: The Multi-Ethnic Study of Atherosclerosis
Authors: Venkat S Manubolu, Vinithra Varadarajan, Jairo Aldana-Bitar, Dhiran Verghese, Luay Alalawi, April Kinninger, Sion Roy, Joao A Ac Lima, Susan R Heckbert, Matthew Budoff
Journal: Circulation (2022)

Introduction: Despite the best risk prediction tools, there seems to be a significant amount of residual risk of atrial fibrillation (AF) that justifies new risk prediction strategies. The CHARGE- AF simple model outperforms other existing models. This study aims to evaluate the predictive ability of cardiac MRI-based imaging biomarkers in addition to the CHARGE AF simple model. Methods: MESA is an observational cohort study of 6,814 men and women from six U.S. communities between the ages of 45 and 84 years, who were initially free of clinical CVD. We included 4185 participants after excluding baseline AF (n=70) and missing values of imaging biomarkers (n=2559) at the baseline exam. Left atrial (LA) volume and left ventricular (LV) volumes were obtained from cardiac MRI measurements. Multivariable Cox regression was used to assess the independent 5/10-year AF predictive ability of imaging biomarkers in addition to the baseline model while adjusting for confounders. Results: 4,185 participants were included in the study. The average age (SD) was 61(±10) years, 47% male, 13% current smokers, and 39% White with a median follow-up of 17 years. Of this population, 19% developed AF. In multivariable regression models, a 1 ml increase in LA volume was significantly associated with a 3 to 10% higher risk of developing AF. Compared to the baseline model (M1, with no imaging biomarker), the 5 /10-year risk prediction of atrial fibrillation was improved after adding the imaging biomarkers for models 2, 3, and 6 (Table 1). The 5 /10 years concordance index for assessing risk prediction increased marginally from 80 / 79% in M1 to 84 / 81%, 84 / 81%, and 84 / 81% in M2, M3 and M6 respectively (all p values &amp;lt 0.0001). Conclusions: The incorporation of MRI-based LA volume index into the CHARGE AF simple model demonstrated a modest improvement in the 5/10-year risk prediction of AF. The clinical benefit should be interpreted with caution due to marginal improvement in risk prediction.